Review of Mavacamten, a New Drug for Hypertrophic Cardiomyopathy

In April 2022, the Food and Drug Administration (FDA) approved mavacamten (CAMZYOS) for treatment of adult patients with symptomatic obstructive hypertrophic cardiomyopathy who have slight or marked limitations in their physical activity (classified by the New York Heart Association [NYHA] as Class II [mild] or III [moderate], respectively).[1]

Although there is no cure for obstructive hypertrophic cardiomyopathy, patients typically do not require any treatment as long as they do not experience symptoms such as shortness of breath, fatigue, chest pain, palpitations or fainting (syncope).[2],[3] The severity of symptoms can vary, but they often reduce patients’ quality of life and in rare cases can even cause sudden death.[4] However, there are several treatments and FDA-approved medications available to help patients manage their symptoms.

Mavacamten is one of these medications. Patients taking this newly approved drug need to be carefully monitored before their first dose and regularly during the entire duration of their treatment because this drug itself can cause heart failure, especially when taken concomitantly (at the same time) with several other drugs, as discussed in more detail below.[5] Due to the possible harms associated with the new drug and because many patients achieve a good quality of life with other available treatments that have better known safety profiles, Public Citizen’s Health Research Group has classified mavacamten as Do Not Use For Seven Years.

What is obstructive hypertrophic cardiomyopathy?

Hypertrophic cardiomyopathy is a genetic disease that causes the muscles in the heart to thicken.[6],[7] This condition is called non-obstructive hypertrophic cardiomyopathy when the thickening of the heart muscles does not block or obstruct the flow of blood from the lower left heart chamber to the body. However, most patients have obstructive hypertrophic cardiomyopathy, meaning the thickened heart muscles do partially block or obstruct the flow of blood from the lower left heart chamber.

Hypertrophic cardiomyopathy does not always cause symptoms. However, if the heart muscle becomes too bulky and stiff or causes significant blood-flow obstruction, it becomes more difficult for the heart to pump blood into the body, and patients can begin to experience symptoms.[8]

To help relieve these symptoms, physicians can prescribe one or more of the following medications: a beta-blocker, such as metoprolol (KAPSPARGO SPRINKLE, LOPRESSOR, TOPROL-XL); a non-dihydropyridine calcium channel blocker, such as verapamil (CALAN SR, VERELAN); and disopyramide (NORPACE).[9],[10] For those patients who do not respond well to these drugs, there are also surgical and nonsurgical options to remove parts of the thickened heart muscle. These drugs and therapies can help most patients to have a good quality of life and a normal life span.

Evidence on effectiveness of mavacamten

The FDA approved mavacamten based primarily on only one placebo-controlled clinical trial, in which 251 adults with obstructive hypertrophic cardiomyopathy with NYHA class II or III symptoms were randomly assigned to receive either mavacamten or placebo in addition to the beta-blocker or the calcium channel blocker they were already taking.[11],[12]

After 30 weeks of treatment, patients taking the new drug were more than twice as likely (37%) to have improvements in either their exercise capacity and symptoms (as measured by a reduction in NYHA class) or their peak oxygen consumption (a measure of heart and lung function combined) than those taking the placebo (17%).[13]

Importantly, the clinical trial did not include a control group that received standard combination drug therapy for obstructive hypertrophic cardiomyopathy, such as a beta blocker or calcium channel blocker plus disopyramide or a beta blocker plus a calcium channel blocker.

Important adverse events

The product labeling for mavacamten includes an FDA-required black-box warning — the agency’s most prominent warning — because this drug can impair the lower left heart chamber’s ability to pump enough blood into the body (systolic dysfunction). This can cause serious or life-threatening heart failure.[14] Patients who develop other serious illnesses, such as a severe infection or abnormal heart rhythms (including atrial fibrillation), are at greatest risk of systolic dysfunction and heart failure with mavacamten.

For this reason, patients may need to either stop taking the drug temporarily, take a reduced dose or discontinue the drug permanently, for example when the proportion of blood that the heart can pump from the filled lower left chamber drops below 50%.[15] Patients also need to avoid certain over-the-counter and prescription medications that interfere with how the new drug is metabolized (broken down) in the body, such as omeprazole (KONVOMEP, PRILOSEC, TALICIA, ZEGERID), esomeprazole (NEXIUM, VIMOVO) and cimetidine (TAGAMET HB).

These risks can be reduced with careful monitoring of how the patient’s heart responds to the drug, for example through a heart imaging test called an echocardiogram before the first dose and at regular intervals during the treatment.[16] However, even with such monitoring, the rate of serious adverse events involving heart failure or systolic dysfunction was 70% higher in mavacamten-group subjects than in placebo-group subjects.[17] Additionally, subjects receiving mavacamten were more likely than those receiving a placebo to feel dizzy (27% and 18%, respectively) and to faint (6% and 2%, respectively).

Therefore, the FDA only approved mavacamten with a risk evaluation and mitigation strategy in place. This means that patients who are prescribed this drug need to be carefully monitored throughout their treatment so that the dosage can be reduced or the drug discontinued if necessary.

Risk–benefit assessment

The FDA estimated that for every 140 treated patients taking mavacamten, 28 will experience improvements (based on 30 weeks of treatment) and one will suffer from a serious adverse event (based on approximately one year of treatment).[18] In addition, the FDA argued that “patients who do not experience meaningful improvements of their symptoms with mavacamten would be expected to discontinue the drug given the complex monitoring required.”[19]

However, because mavacamten is a first-in-class drug, it is concerning that the single clinical trial on which its approval was primarily based had several notable limitations, including the relatively small number of subjects enrolled and the trial’s short duration. These factors greatly limit our understanding of the risks and benefits of the drug. Most importantly, patients who were being treated with the drug disopyramide or who were taking both a beta-blocker and a calcium channel blocker were excluded from this trial.[20] Thus, the trial did not compare the benefits and risks of mavacamten to those of standard combination drug therapy for obstructive hypertrophic cardiomyopathy.

There is also no information available yet on whether or not this drug causes harm to a fetus during pregnancy or can increase the risk of cancer.[21]

What You Can Do

If you are diagnosed with obstructive hypertrophic cardiomyopathy and suffer from symptoms, consult your doctor about whether beta-blockers, calcium channel blockers, disopyramide or some combination of these drugs can help relieve your symptoms.

If you are already taking mavacamten, talk to you doctor about transitioning to other available treatments that have better known safety profiles. Do not discontinue this drug without speaking to your doctor first. Until you transition to alternative treatment, make sure that you are closely monitored throughout your treatment with the drug. Tell your doctor all the medications and supplements you are taking and let them know every time before you start taking any new drug, because mavacamten can cause serious harm if taken together with prescription or over-the-counter medications, or even with grapefruit juice.
 

References

[1] Food and Drug Administration. Center for Drug Evaluation and Research. Approval package for application number 214998Orig1s000. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/214998Orig1s000Approv.pdf. Accessed February 8, 2023.

[2] Patient education: Hypertrophic cardiomyopathy in adults (The basics). UpToDate. Updated July 12, 2021.

[3] Patient education: Hypertrophic cardiomyopathy (Beyond the basics) UpToDate. Updated June 30, 2022.

[4] Food and Drug Administration. FDA approves new drug to improve heart function in adults with rare heart condition. April 29, 2022. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-new-drug-improve-heart-function-adults-rare-heart-condition. Accessed February 8, 2023.

[5] Bristol-Myers Squibb. Label: mavacamten (CAMZYOS). April 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214998s000lbl.pdf. Accessed February 8, 2023.

[6] Patient education: Hypertrophic cardiomyopathy in adults (The basics). UpToDate. Updated July 12, 2021.

[7] Patient education: Hypertrophic cardiomyopathy (Beyond the basics) UpToDate. Updated June 30, 2022.

[8] Mayo Clinic. Hypertrophic cardiomyopathy. May 24, 2022. https://www.mayoclinic.org/diseases-conditions/hypertrophic-cardiomyopathy/symptoms-causes/syc-20350198. Accessed February 8, 2023.

[9] Patient education: Hypertrophic cardiomyopathy (Beyond the basics) UpToDate. Updated June 30, 2022.

[10] Packard E, de Feria A, Peshin S, et al. Contemporary therapies and future directions in the management of hypertrophic cardiomyopathy. Cardiol Ther. 2022;11(4):491-507.

[11] Food and Drug Administration. Center for Drug Evaluation and Research. Clinical and statistical review(s) for application number 214998Orig1s000. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/214998Orig1s000Med_StatR.pdf. Accessed February 8, 2023.

[12] Olivotto I, Oreziak A, Barriales-Villa R, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020;396(10253):759-769.>

[13] Ibid.

[14] Bristol Myers Squibb. Label: mavacamten (CAMZYOS). April 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214998s000lbl.pdf. Accessed February 8, 2023.

[15] Food and Drug Administration. Center for Drug Evaluation and Research. Risk assessment and risk mitigation review(s) for application number 214998Orig1s000. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/214998Orig1s000RiskR.pdf. Accessed February 8, 2023.

[16] Ibid.

[17] Food and Drug Administration. Center for Drug Evaluation and Research. Clinical and statistical review(s) for application number 214998Orig1s000. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/214998Orig1s000Med_StatR.pdf. Accessed February 8, 2023.

[18] Ibid.

[19] Ibid.

[20] Olivotto I, Oreziak A, Barriales-Villa R, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020;396(10253):759-769.

[21] Food and Drug Administration. Center for Drug Evaluation and Research. Clinical and statistical review(s) for application number 214998Orig1s000. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/214998Orig1s000Med_StatR.pdf. Accessed February 8, 2023.